Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Zoledronic acid Mylan 4 mg/5 ml concentrate for solution for infusion
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial with 5 ml concentrate contains 4 mg zoledronic acid (as monohydrate). One ml concentrate contains 0.8 mg zoledronic acid (as monohydrate).
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear and colourless solution.
4.CLINICAL PARTICULARS
4.1. | Therapeutic indications |
- | Prevention of skeletal related events (pathological fractures, spinal compression, radiation or |
| surgery to bone, or |
| malignancies involving bone. |
- | Treatment of adult patients with |
4.2. | Posology and method of administration |
Zoledronic acid Mylan must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zoledronic acid Mylan should be given the package leaflet and the patient reminder card.
Posology
Prevention of skeletal related events in patients with advanced malignancies involving bone Adults and elderly people
The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid every 3 to 4 weeks.
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is
Treatment of TIH
Adults and elderly people
The recommended dose in hypercalcaemia

Renal impairment TIH:
Zoledronic acid treatment in TIH patients who also have severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine > 400 μmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in TIH patients with serum creatinine < 400 μmol/l or < 4.5 mg/dl (see section 4.4).
Prevention of skeletal related events in patients with advanced malignancies involving bone:
When initiating treatment with zoledronic acid in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should be determined. CLcr is calculated from serum creatinine using the
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CLcr
Baseline creatinine clearance (ml/min) | Zoledronic acid recommended dose* |
> 60 | 4.0 mg zoledronic acid |
3.5 mg* zoledronic acid | |
3.3 mg* zoledronic acid | |
3.0 mg* zoledronic acid |
*Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr=75 ml/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min.
Following initiation of therapy, serum creatinine should be measured prior to each dose of zoledronic acid and treatment should be withheld if renal function has deteriorated. In the clinical trials, renal deterioration was defined as follows:
-For patients with normal baseline serum creatinine (< 1.4 mg/dl or < 124 μmol/l), an increase of
0.5mg/dl or 44 μmol/l;
-For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 μmol/l), an increase of
1.0mg/dl or 88 μmol/l.
In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returned to within 10% of the baseline value (see section 4.4). Zoledronic acid treatment should be resumed at the same dose as that given prior to treatment interruption.
Paediatric population
The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Method of administration Intravenous use.
Zoledronic acid Mylan 4 mg/5 ml concentrate for solution for infusion, further diluted in 100 ml (see section 6.6), should be given as a single intravenous infusion in no less than 15 minutes.
In patients with mild to moderate renal impairment, reduced zoledronic acid doses are recommended
(see section “Posology” above and section 4.4).
Instructions for preparing reduced doses of Zoledronic acid Mylan
Withdraw an appropriate volume of the concentrate needed, as follows:
-4.4 ml for 3.5 mg dose
-4.1 ml for 3.3 mg dose
-3.8 ml for 3.0 mg dose
For instructions on the dilution of the medicinal product before administration, see section 6.6. The withdrawn amount of concentrate must be further diluted in 100 ml of sterile sodium chloride 9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution. The dose must be given as a single intravenous infusion over no less than 15 minutes.
Zoledronic acid Mylan concentrate must not be mixed with calcium or other divalent
Patients must be maintained well hydrated prior to and following administration of zoledronic acid.
4.3. | Contraindications |
| Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients |
| listed in section 6.1 |
| |
4.4. | Special warnings and precautions for use |
General
Patients must be assessed prior to administration of zoledronic acid to ensure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard
Zoledronic acid Mylan contains the same active substance as found in medicinal products indicated for treatment of osteoporosis and Paget´s disease of the bone. Patients being treated with Zoledronic acid Mylan should not be treated with such medicinal products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Renal insufficiency
Patients with TIH and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with zoledronic acid outweighs the possible risk.
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is
Zoledronic acid has been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration,
of zoledronic acid at recommended doses for prevention of skeletal related events, although less frequently.
Patients should have their serum creatinine levels assessed prior to each dose of zoledronic acid. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of zoledronic acid are recommended. In patients who show evidence of renal deterioration during treatment, zoledronic acid should be withheld. Zoledronic acid should only be resumed when serum creatinine returns to within 10% of baseline. Zoledronic acid treatment should be resumed at the same dose as that given prior to treatment interruption.
In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data in patients with severe renal impairment (in clinical trials defined as serum creatinine ≥ 400 μmol/l or ≥ 4.5 mg/dl for patients with TIH and ≥ 265 μmol/l or ≥ 3.0 mg/dl for patients with cancer and bone metastases, respectively) at baseline and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30 ml/min), the use of zoledronic acid is not recommended in patients with severe renal impairment.
Hepatic insufficiency
As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials and in the post marketing setting in patients receiving zoledronic acid.
The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth, except in medical emergency situations. A dental examination with appropriate preventive dentistry and an individual
The following risk factors should be considered when evaluating an individual’s risk of developing
ONJ:
-Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate.
-Cancer, co morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
-Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids.
-History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting dentures.
All patients should be encouraged to maintain good oral hygiene, undergo routine dental
While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to zoledronic acid administration. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with
Musculoskeletal pain
In
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Hypocalcaemia
Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (including convulsions, hypoaesthesia and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, the hypocalcaemia may be
Zoledronic acid Mylan contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially
4.5.Interaction with other medicinal products and other forms of interaction
In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see section 5.2), but no formal clinical interaction studies have been performed.
Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required (see section 4.4).
Caution is indicated when zoledronic acid is used with other potentially nephrotoxic medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.
In multiple myeloma patients, the risk of renal dysfunction may be increased when zoledronic acid is used in combination with thalidomide.
Caution is advised when zoledronic acid is administered with
4.6.Fertility, pregnancy and lactation
Pregnancy
There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Zoledronic acid should not be used during pregnancy. Women of
It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid is contraindicated in
Fertility
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered to be related to the
compound’s inhibition of skeletal calcium metabolisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of zoledronic acid on fertility in humans.
4.7.Effects on ability to drive and use machines
Adverse reactions, such as dizziness and somnolence, may have influence on the ability to drive or use machines, therefore caution should be exercised with the use of Zoledronic acid Mylan along with driving and operating of machinery.
4.8.Undesirable effects
Summary of the safety profile
Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions).
The following are the important identified risks with zoledronic acid in the approved indications: Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are shown in Table 1.
Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and
Table 1
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders |
|
Common: | Anaemia |
Uncommon: | Thrombocytopenia, leukopenia |
Rare: | Pancytopenia |
Immune system disorders |
|
Uncommon: | Hypersensitivity reaction |
Rare: | Angioneurotic oedema |
Psychiatric disorders |
|
Uncommon: | Anxiety, sleep disturbance |
Rare: | Confusion |
Nervous system disorders |
|
Common: | Headache |
Uncommon: | Dizziness, paraesthesia, dysgeusia, |
| hypoaesthesia, hyperaesthesia, tremor, |
| somnolence |
Very rare: | Convulsions, hypoaesthesia and tetany |
| (secondary to hypocalcaemia) |
Eye disorders |
|
Common: | Conjunctivitis |
Uncommon: | Blurred vision, scleritis and orbital |
| inflammation |
Rare: | Uveitis |
Very rare: | Episcleritis |
Cardiac disorders |
|
Uncommon: | Hypertension, hypotension, atrial fibrillation, |
| hypotension leading to syncope or |
| circulatory collapse |
Rare: | Bradycardia, cardiac arrhythmia (secondary |
| to hypocalcaemia) |
Respiratory, thoracic and mediastinal disorders |
|
Uncommon: | Dyspnoea, cough, bronchoconstriction |
Rare: | Interstitial lung disease |
Gastrointestinal disorders |
|
Common: | Nausea, vomiting, decreased appetite |
Uncommon: | Diarrhoea, constipation, abdominal pain, |
| dyspepsia, stomatitis, dry mouth |
Skin and subcutaneous tissue disorders |
|
Uncommon: | Pruritus, rash (including erythematous and |
| macular rash), increased sweating |
Musculoskeletal and connective tissue disorders |
|
Common: | Bone pain, myalgia, arthralgia, generalised |
| pain |
Uncommon: | Muscle spasms, osteonecrosis of the jaw |
Very rare: | Osteonecrosis of the external auditory canal |
| (bisphosphonate class adverse reaction) |
Renal and urinary disorders |
|
Common: | Renal impairment |
Uncommon: | Acute renal failure, haematuria, proteinuria |
Rare: | Acquired Fanconi syndrome |
General disorders and administration site conditions |
|
Common: | Fever, |
| rigors, malaise and flushing) |
Uncommon: | Asthenia, peripheral oedema, injection site |
| reactions (including pain, irritation, swelling, |
| induration), chest pain, weight increase, |
| anaphylactic reaction/shock, urticaria |
Rare: | Arthritis and joint swelling as a symptom of |
| acute phase reaction |
Investigations |
|
Very common: | Hypophosphataemia |
Common: | Blood creatinine and blood urea increased, |
| hypocalcaemia |
Uncommon: | Hypomagnesaemia, hypokalaemia |
Rare: | Hyperkalaemia, hypernatraemia |
Description of selected adverse reactions
Renal function impairment
Zoledronic acid has been associated with reports of renal dysfunction. In a pooled analysis of safety data from zoledronic acid registration trials for the prevention of
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as zoledronic acid (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.
Atrial fibrillation
In one
Acute phase reaction
This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea, arthralgia and arthritis with subsequent joint swelling. The onset time is ≤ 3 days
- Mysildecard - MYLAN S.A.S.
- Atazanavir mylan - MYLAN S.A.S.
- Clopidogrel mylan - Mylan S.A.S.
- Zonisamide mylan - Mylan S.A.S.
- Cinacalcet mylan - Mylan S.A.S.
Prescription drugs listed. Manufacturer: "Mylan S.A.S."

Atypical fractures of the femur
During
Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Based on the review of both clinical trial and
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9.Overdose
Clinical experience with acute overdose of zoledronic acid is limited. The administration of doses up to 48 mg of zoledronic acid in error has been reported. Patients who have received doses higher than those recommended (see section 4.2) should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.
5.PHARMACOLOGICAL PROPERTIES
5.1.Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In
In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several
-In vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment, making it less conducive to tumour cell growth,
-In vitro: Inhibition of osteoblast proliferation, direct cytostatic and
Clinical trial results in the prevention of skeletal related events in patients with advanced malignancies involving bone
The first randomised,
In a second study including solid tumours other than breast or prostate cancer, zoledronic acid 4 mg significantly reduced the proportion of patients with an SRE, delayed the median time to first SRE by > 2 months, and reduced the skeletal morbidity rate. Multiple event analysis showed 30.7% risk reduction in developing SREs in the zoledronic acid 4 mg group compared with placebo. Efficacy results are provided in Table 3.
Table 2: Efficacy results (prostate cancer patients receiving hormonal therapy)
| Any SRE (+TIH) | Fractures* | Radiation therapy to | ||||||
|
|
|
|
|
|
| bone |
| |
| zoledronic |
| Placebo | zoledronic |
| Placebo | zoledronic |
| Placebo |
| acid 4 mg |
|
| acid 4 mg |
|
| acid 4 mg |
|
|
N |
|
|
| ||||||
Proportion of patients |
|
|
| ||||||
with SREs (%) |
|
|
|
|
|
|
|
|
|
0.028 |
| 0.052 |
| 0.119 |
| ||||
Median time to SRE |
| NR |
| NR | NR |
| |||
(days) |
|
|
|
|
|
|
|
|
|
0.009 |
| 0.020 |
| 0.055 |
| ||||
Skeletal morbidity | 0.77 |
| 1.47 | 0.20 |
| 0.45 | 0.42 |
| 0.89 |
rate |
|
|
|
|
|
|
|
|
|
0.005 |
| 0.023 |
| 0.060 |
| ||||
Risk reduction of |
| - | NA |
| NA | NA |
| NA | |
suffering from |
|
|
|
|
|
|
|
|
|
multiple events** (%) |
|
|
|
|
|
|
|
|
|
0.002 |
| NA |
| NA |
|
*Includes vertebral and
**Accounts for all skeletal events, the total number as well as time to each event during the trial
NR | Not Reached |
NA | Not Applicable |
Table 3: Efficacy results (solid tumours other than breast or prostate cancer)
| Any SRE (+TIH) | Fractures* | Radiation therapy to | ||||||
|
|
|
|
|
|
| bone |
| |
| zoledronic |
| Placebo | zoledronic |
| Placebo | zoledronic |
| Placebo |
| acid 4 mg |
|
| acid 4 mg |
|
| acid 4 mg |
|
|
N |
|
|
| ||||||
Proportion of patients |
|
|
| ||||||
with SREs (%) |
|
|
|
|
|
|
|
|
|
0.039 |
| 0.064 |
| 0.173 |
| ||||
Median time to SRE |
| NR |
| NR |
| ||||
(days) |
|
|
|
|
|
|
|
|
|
0.009 |
| 0.020 |
| 0.079 |
| ||||
Skeletal morbidity | 1.74 |
| 2.71 | 0.39 |
| 0.63 | 1.24 |
| 1.89 |
rate |
|
|
|
|
|
|
|
|
|
0.012 |
| 0.066 |
| 0.099 |
| ||||
Risk reduction of | 30.7 |
| - | NA |
| NA | NA |
| NA |
suffering from |
|
|
|
|
|
|
|
|
|
multiple events** (%) |
|
|
|
|
|
|
|
|
|
0.003 |
| NA |
| NA |
|
*Includes vertebral and
**Accounts for all skeletal events, the total number as well as time to each event during the trial
NR | Not Reached |
NA | Not Applicable |
In a third phase III randomised,
Table 4: Efficacy results (breast cancer and multiple myeloma patients)
| Any SRE (+TIH) | Fractures* | Radiation therapy to | ||||||
|
|
|
|
|
|
| bone |
| |
| zoledronic |
| Pam | zoledronic |
| Pam | zoledronic |
| Pam |
| acid 4 mg |
| 90 mg | acid 4 mg |
| 90 mg | acid 4 mg |
| 90 mg |
N |
|
|
| ||||||
Proportion of patients |
|
|
| ||||||
with SREs (%) |
|
|
|
|
|
|
|
|
|
0.198 |
| 0.653 |
| 0.037 |
| ||||
Median time to SRE |
| NR |
| NR |
| NR | |||
(days) |
|
|
|
|
|
|
|
|
|
0.151 |
| 0.672 |
| 0.026 |
| ||||
Skeletal morbidity | 1.04 |
| 1.39 | 0.53 |
| 0.60 | 0.47 |
| 0.71 |
rate |
|
|
|
|
|
|
|
|
|
0.084 |
| 0.614 |
| 0.015 |
| ||||
Risk reduction of |
| - | NA |
| NA | NA |
| NA | |
suffering from |
|
|
|
|
|
|
|
|
|
multiple events** (%) |
|
|
|
|
|
|
|
|
|
0.030 |
| NA |
| NA |
|
*Includes vertebral and
**Accounts for all skeletal events, the total number as well as time to each event during the trial
NR | Not Reached |
NA | Not Applicable |
Zoledronic acid 4 mg was also studied in a
Patients received either 4 mg zoledronic acid or placebo every four weeks for one year. Patients were evenly distributed between zoledronic
The SRE rate (events/person year) was 0.628 for zoledronic acid and 1.096 for placebo. The proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the zoledronic
In the zoledronic

Figure 1. Mean changes from baseline in BPI scores. Statistically significant differences are marked (*p< 0.05) for between treatment comparisons (4 mg zoledronic acid vs. Placebo)
Clinical trial results in the treatment of TIH
Clinical studies in
To assess the effects of 4 mg zoledronic acid versus pamidronate 90 mg, the results of two pivotal multicentre studies in patients with TIH were combined in a
Table 5: Proportion of complete responders by day in the combined TIH studies
| Day 4 |
| Day 7 | Day 10 |
Zoledronic acid 4 mg (N=86) | 45.3% | (p=0.104) | 82.6% (p=0.005)* | 88.4% (p=0.002)* |
Zoledronic acid 8 mg (N=90) | 55.6% | (p=0.021)* | 83.3% (p=0.010)* | 86.7% (p=0.015)* |
Pamidronate 90 mg (N=99) | 33.3% |
| 63.6% | 69.7% |
Median time to normocalcaemia was 4 days. Median time to relapse
17 days for those treated with pamidronate 90 mg
In clinical trials 69 patients who relapsed or were refractory to initial treatment (zoledronic acid 4 mg, 8 mg or pamidronate 90 mg) were retreated with 8 mg zoledronic acid. The response rate in these patients was about 52%. Since those patients were retreated with the 8 mg dose only, there are no data available allowing comparison with the 4 mg zoledronic acid dose.
In clinical trials performed in patients with
Paediatric population
Clinical trial results in the treatment of severe osteogenesis imperfecta in paediatric patients aged 1 to 17 years
The effects of intravenous zoledronic acid in the treatment of paediatric patients (age 1 to 17 years) with severe osteogenesis imperfecta (types I, III and IV) were compared to intravenous pamidronate in one international, multicentre, randomised,
The primary endpoint of the study was the percent change from baseline in lumbar spine bone mineral density (BMD) after 12 months of treatment. Estimated treatment effects on BMD were similar, but the trial design was not sufficiently robust to establish
The type of adverse reactions observed in this population were similar to those previously seen in adults with advanced malignancies involving the bone (see section 4.8). The adverse reactions ranked under headings of frequency, are presented in Table 6. The following conventional classification is used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare
(≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Table 6: Adverse reactions observed in paediatric patients with severe osteogenesis imperfecta1
Nervous system disorders |
|
Common: | Headache |
Cardiac disorders |
|
Common: | Tachycardia |
Respiratory, thoracic and mediastinal disorders |
|
Common: | Nasopharyngitis |
Gastrointestinal disorders |
|
Very common: | Vomiting, nausea |
Common: | Abdominal pain |
Musculoskeletal and connective tissue disorders |
|
Common: | Pain in extremities, arthralgia, musculoskeletal |
| pain |
General disorders and administration site conditions |
|
Very common: | Pyrexia, fatigue |
Common: | Acute phase reaction, pain |
Investigations |
|
Very common: | Hypocalcaemia |
Common: | Hypophosphataemia |
1 Adverse events occurring with frequencies < 5% were medically assessed and it was shown that these cases are consistent with the well established safety profile of zoledronic acid (see section 4.8)
In paediatric patients with severe osteogenesis imperfecta, zoledronic acid seems to be associated with more pronounced risks for acute phase reaction, hypocalcaemia and unexplained tachycardia, in comparison to pamidronate, but this difference declined after subsequent infusions.
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing zoledronic acid in all subsets of the paediatric population in the treatment of
5.2.Pharmacokinetic properties
Single and multiple 5- and
After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the second infusion of zoledronic acid on day 28.
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with
The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen with other bisphosphonates.
- Zoledronic acid teva - M05BA08
- Zoledronic acid teva generics - M05BA08
- Zoledronic acid teva pharma - M05BA08
- Zoledronic acid hospira - M05BA08
- Zoledronic acid actavis - M05BA08
Prescription drugs listed. ATC Code: "M05BA08"
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro, shows no biotransformation and in animal studies < 3% of the administered dose was recovered in the faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 cancer patients studied. Population analysis showed that for a patient with creatinine clearance of 20 ml/min (severe renal impairment), or 50 ml/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, of that of a patient showing creatinine clearance of 84 ml/min. Only limited pharmacokinetic data are available in patients with severe renal insufficiency (creatinine clearance < 30 ml/min).
In an in vitro study, zoledronic acid showed low affinity for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/ml to 5000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at
2 ng/ml to 77% at 2000 ng/ml of zoledronic acid.
Special populations
Paediatric patients
Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.
5.3.Preclinical safety data
Acute toxicity
The highest
Subchronic and chronic toxicity
Zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously in rats and 0.005 mg/kg intravenously once every
The most frequent finding in
The safety margins relative to renal effects were narrow in the
Reproduction toxicity
Zoledronic acid was teratogenic in the rat at subcutaneous doses ≥ 0.2 mg/kg. Although no teratogenicity or foetotoxicity was observed in the rabbit, maternal toxicity was found. Dystocia was observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat.
Mutagenicity and carcinogenic potential
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
6.PHARMACEUTICAL PARTICULARS
6.1.List of excipients
Sodium citrate
Sodium hydroxide
Hydrochloric acid
Water for injections
6.2.Incompatibilities
To avoid potential incompatibilities, Zoledronic acid Mylan concentrate is to be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution.
This medicinal product must not be mixed with calcium or other divalent
Studies with polyolefin bags (prefilled with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution), showed no incompatibility with Zoledronic acid Mylan.
6.3.Shelf life
2 years.
After dilution: Chemical and physical
5% w/v glucose solution (minimal concentration: 3 mg/100 ml; maximal concentration: 4 mg/100 ml). From a microbiological point of view, the product should be used immediately. If not used immediately,
6.4.Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5.Nature and contents of container
15 ml colourless type I glass vial with a bromobutyl rubber stopper and an aluminium crimp cap with plastic
Each vial contains 5 ml of concentrate.
Packs containing 1, 4 or 10 vials or multipacks containing 4 (4 cartons of 1) vials.
Not all pack sizes may be marketed.
6.6.Special precautions for disposal and other handling
Prior to administration, 5 ml concentrate from one vial or the volume of the concentrate withdrawn as required must be further diluted with 100 ml of
9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution).
Additional information on handling of Zoledronic acid Mylan, including guidance on preparation of reduced doses, is provided in section 4.2.
Aseptic techniques must be followed during the preparation of the infusion. For single use only.
Only clear solution free from particles and discolouration should be used.
Healthcare professionals are advised not to dispose of unused Zoledronic acid Mylan via the domestic sewage system.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Mylan S.A.S.
117 Allée des Parcs
69800 Saint Priest France
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23.08.2012
Date of latest renewal:
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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